Although all B lymphocytes were originally thought to belong to a single lineage, our recent studies distinguish two murine B cell lineage derived from independent progenitors residing in different locations in adult animals. The more conventional of these lineages, which derives from progenitors in adult bone marrow, contains most of the B cells in the animal and has most of the properties traditionally associated with B cells. The other lineage (Ly-1 B), which derives from self-renewing progenitors in adult peritoneum, is strikingly different from conventional B cells, e.g., with respect to size, surface markers, depletion by neonatal anti Ig treatments, genetically controlled elevations and deficiencies. In addition, it is functionally distinct in that it produces most of the IggM autoantibodies in normal and autoimmune animals. In the studies proposed here, we plan to continue the physical and functional characterization of these B cell lineages. At the molecular level, we will investigate several novel genetic mechanisms that determine Ig structure in Ly-1 B tumors and perhaps in normal cells (V/H) gene replacement, preferential V/H gene utilization, kappa/lambda light chain shifts). At the functional level, we will compare lineage contributions to antibody responses and serum Ig levels in normal and immunodefective animals. Finally, at the whole animal level, we shall define the role of Ly-1 B cells in autoimmune disease and explore the recently detected relationship between Ly-1 B cells and the induction of chronic allotype suppression in animals exposed perinatally to maternal antibodies to paternal allotypes. These latter studies are particularly germaine to the long-term interests of this project, which is concerned with recognizing (and perhaps preventing) immunological defects caused by maternal antibodies tht pass the fetal-maternal barrier.